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Polyphor POL7080 And The Journey to The Land of Pyocyanea (Part 1)

When Roche inlicensed Polyphor’s anti-pseudomonas drug POL7080 in November 2013, it marked a turning point. It seemed that Big Pharma that had all but abandoned the field in the last decade and was getting engaged in anti-infectives again. When a company with as much experience in antibiotic drug development as Roche sees value even in a narrow-spectrum specialty drug, there is hope that others will follow.

Roche then acquired a Phase I beta-lactamase inhibitor OP-0595 from Meiji / Fedora early in 2015. Also known as FPI-1459, it has now been christened as Roche / Genentech drug RG-6080. This is a diazabicyclooctane beta-lactamase inhibitor (BLI) which does not have a beta-lactam ring structure. We are not told what other beta-lactam drug will be combined with it.

POL7080 has also been renamed, it now goes by the new moniker RG7929. I will continue to call it POL7080 here just for convenience because this renaming game is simply getting out of hand. Many companies keep at least the compound number designation constant but many do not. GSK, Novartis, Roche and others have their own ways of confusing the ancestry (and the reviewers); in published information the drug may even be referred to under a code name. OK, back to POL7080.

Let’s briefly review the attributes which make POL7080 such an interesting compound: First, it is a totally novel drug, with a MoA we never heard of before. The target is LptD, also called OstA, which is an essential outer membrane protein.[1] The drug is a synthetic cyclopeptide and peptidomimetic and hence an IV drug only[2],[3] It has excellent bactericidal activity against P. aeruginosa: MICs are consistently in the <0.5 mg/L range. While Providencia species are susceptible as well, S. maltophilia and B. cepacia are not and neither are other Gram-negatives.[4]

In a mouse septicemia model using two P. aeruginosa strains, POL7080 reduced mortality.[5] In a murine P. aeruginosa pneumonia model, the drug worked against MDR and non-MDR P. aeruginosa strains, but tissue log CFUs reductions were not all that impressive.[6]

An SAD / MAD Phase I study for safety and PK was conducted in 52 healthy volunteers. Maximum exposures were 10 mg/kg/day for the SD, and 2 mg/kg q8h (6 mg/kg/day) for the MD cohorts. The max. duration of exposure was 6 days. POL7080 was given IV q12h or q8h, with 2-3 hour infusion times. A summary of Phase 1 findings is available in abstract form only but we are told that renal excretion is the main route of elimination and that despite a long half-life no significant accumulation was observed. Like other cationic molecules, e.g., aminoglycosides (AG), proximal tubular reuptake is via the megalin receptor.[7] Hence, drug-drug interaction with colistin and AGs are to be expected, making such combinations problematic.

The authors state that no significant side effects were seen in Phase 1 studies.NB: Such bland boilerplate proclamations of safety have become a standard fixture of company press releases and early abstracts; let’s wait for further human data before accepting this as more than a ‘forward looking statement’. Somebody please explain why the infusion has to be administered so slowly? How about the history of the protegrin class which is known for hemolysis? Anyway, let’s move on.

Details of the serum PK profile have not been published, only interpretations of the data. Based on PK/PD modeling and PopPK a dose of 7.5 mg/kg per day for treatment of “VAP patients with normal renal function” should be adequate for pathogens up to an MIC of 1 mg/L. This daily dose is obviously higher than the doses tested in Phase 1. As we know from painful experience, ICU and VAP patients have significantly altered PK, with higher Vd requiring higher dosing. This was considered in the Monte-Carlo simulations; hence, the recommendation is for doses of 200 mg IV q8h (or higher) in this patient population.[8] When you do the math this means that 10-12 mg/kg/day may actually be required.

In November 2014, POL7080 became a QIDP drug, a designation from FDA which this drug deserves more than most recent nominees (which include SYM-1219 for bacterial vaginosis!).

Since its acquisition, Roche has moved the drug into Phase 2 starting with a few rather small PK and safety studies.

But it remains unclear in which major population Roche will conduct its efficacy testing for POL7080. Polyphor indicated that it would want the drug to be developed in “VABP caused by P. aeruginosa”. If this is the chosen indication for Phase 3, it will need a very unorthodox and innovative development path, both by regulatory and clinical standards.

We will address these options and the VABP ‘minefield’ in Part 2 of this blog.